LincRNA-p21 knockdown reversed tumor-associated macrophages function by promoting MDM2 to antagonize p53 activation and alleviate breast cancer development

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2020-05, Vol.69 (5), p.835-846
• Main Authors: Zhou, Lining, Tian, Yu, Guo, Fang, Yu, Bin, Li, Jiali, Xu, Huaxi, Su, Zhaoliang
• Format: Article
• Language: English
• Subjects: Adoptive transfer; Animals; Apoptosis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - immunology; Breast Neoplasms - pathology; Cancer Research; Cell adhesion & migration; Cell Line, Tumor - transplantation; Cyclin-dependent kinase inhibitor p21; Disease Models, Animal; Female; Flow cytometry; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - immunology; Gene Knockdown Techniques; Humans; Immune system; Immunofluorescence; Immunology; Inflammation; Leukocyte migration; Localization; Macrophages; Macrophages - immunology; MDM2 protein; Medicine; Medicine & Public Health; Metastases; Mice; Monocytes; NF-κB protein; Oligonucleotide Array Sequence Analysis; Oncology; Original; Original Article; p53 Protein; Phenotypes; Primary Cell Culture; Proteasomes; Proteolysis; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Signal Transduction - genetics; Signal Transduction - immunology; Stat3 protein; Surface markers; Therapeutic applications; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology; Tumor Suppressor Protein p53 - metabolism; Tumors; Up-Regulation
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-020-02511-0

Tumor-associated macrophages (TAMs) are important regulators of the complex interplay between immune system and breast cancer. TAMs fuel the cancer progression and metastasis by reprogramming their specific functional phenotype in cancer settings. Therefore, it is important to clarify the mechanisms of shaping specific functional phenotype of macrophages in tumor milieu. LncRNA profiles of TAMs were identified by LncRNA microarray. Flow cytometry was used to detect the surface markers of TAMs. The co-localization among lincRNA-p21, p53 and Mouse Double Minute 2 (MDM2) was identified by FISH probe and immunofluorescence. PyVT-MMTV and BALB/c mice were used for in vivo analysis. In the present work, we found that lincRNA-p21 significantly up-regulated in 4T1 educated macrophages. LincRNA-p21 knockdown facilitated macrophage polarization into pro-inflammatory M1 in tumor microenvironment, which might be caused by MDM2 eliciting proteasome-dependent degradation to p53 and activated NF-κB and STAT3 pathway. TAMs with lincRNA-p21 knockdown induced cancer cell apoptosis, inhibited tumor cell migration and invasion. In vivo, lincRNA-p21 knockdown macrophage adoptive transfer could alleviate breast cancer progression. Our results indicated that lincRNA-p21 was a key regulator of TAMs function in tumor milieu. Our data also shed a light on novel therapeutic targets of tumors characterized by monocytes/macrophages infiltration.